Influence of periostin on bone marrow-derived cell contribution to dermal wound repair.

摘要

Originally thought to function only as a scaffold, the extracellular matrix (ECM) is now understood to provide signals that regulate all aspects of cellular phenotype. Matricellular proteins are a subset of ECM-related molecules defined by their ability to modulate interactions between cells and the ECM. Periostin was recently classified as a matricellular protein based on its expression and function during development and wound repair. Periostin has been shown to influence cell behavior and collagen fibrillogenesis in several tissue types. In this study, we examined how periostin expression influences fibrocyte behavior after dermal injury using periostin null (Pstn -/-) and wild-type (WT) mice. Both periostin upregulation and fibrocyte infiltration have previously been shown to accelerate dermal closure after acute injury and to promote excessive scarring in fibrotic tissues. We found that periostin expression elevates fibrocyte levels in murine dermal wounds during wound contraction and at late stages of tissue remodeling. This suggests a novel mechanism by which periostin expression may accelerate the closure of dermal wounds as reported by other investigators and increase collagen accumulation in dermal scar tissue as demonstrated in this work. Periostin upregulation was also found to elevate circulating fibrocyte levels in the blood, suggesting that the peripheral circulation is a significant source of fibrocytes after dermal injury and that periostin expression influences fibrocyte behavior outside of the dermal wound bed. In vitro analysis of fibrocyte migration revealed that periostin expression also increases CXCL12-induced chemotaxis and integrin-mediated migration on periostin. CXCR4+/collagen type I+ fibrocyte levels were also found to be elevated after dermal injury in WT mice compared to Pstn -/- mice, providing in vivo evidence indicating that periostin upregulation promotes fibrocyte participation in the CXCR4/CXCL12 signaling axis. Evaluation of our findings as well as data presented in previous publications suggests that periostin expression elevates fibrocyte levels in the dermal wound bed and peripheral blood by stimulating the fibroblastic differentiation of fibrocyte precursors and/or increasing the migration of fibrocytes and their precursors into these tissues. Collectively, the work presented in this dissertation demonstrates a novel role for periostin in promoting fibrocyte participation in wound repair, and also suggests that therapeutic strategies aimed at modulating periostin expression may be effective in regulating fibrocyte contribution to wound closure and tissue fibrosis.